Type 2 diabetes constitutes an enormous health burden in the United States, and despite the increasing prevalence of this disease there are still major gaps in understanding the underlying causes. The overall goal of this proposal is to determine the role of the GI hormone glucagon-like peptide 1 (GLP-1) to regulate glucose tolerance in non-diabetic persons and patients with type 2 diabetes. In healthy humans GLP-1 stimulates insulin secretion, and together with other signals arising from the gut during meal absorption, accounts for 30-60% of the insulin secreted. Studies in animals and humans indicate that blocking the action of GLP-1 causes glucose intolerance. In persons with type 2 diabetes, and other forms of abnormal glucose tolerance, the augmentation of insulin secretion by stimuli from the gut, such as GLP-1, is severely impaired. The findings from therapeutic trials of GLP-1 and GLP-1-agonists support the currently favored model that GLP-1 acts as a hormone. However, recent findings by our group and others have shown that GLP-1 may signal primarily through neural pathways, likely originating in the splanchnic bed. Based on this data we propose that the action of endogenous GLP-1 to stimulate insulin secretion is through a neural reflex originating in the immediate distribution of the portal vein. The specific aims of this project will determine: 1) whether the stimulation of insulin secretion by endogenous GLP-1 in humans is mediated by parasympathetic signaling, and whether this mechanism is abnormal in persons with type 2 diabetes; 2) the mechanisms and pathways of neural activation by which endogenous GLP-1 promotes insulin secretion; 3) the effect of hepatic-portal denervation on glucose tolerance and the response to GLP-1. Establishing the role of a neural system by which intestinal GLP-1 acts is important for understanding how post prandial insulin secretion is regulated and why the incretin axis is impaired in diabetic patients. The results of these studies will add to the understanding of the regulation of glucose metabolism by GLP-1 and the incretin axis, and contribute to the development of new strategies to treat type 2 diabetes.